3-bicycloaryl-2-aminomethyl bicycloalkanes as serotonine reuptake inhibitors

ABSTRACT

A pharmaceutical compound of formula (I) in which R 1  and R 2  are each hydrogen or C 1-4  alkyl, or R 1  and R 2  together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholino group, said group being optionally substituted with 1 to 3 C 1-4 alkyl substituents, R 3  is a naphythyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, quinolinyl or isoquinolinyl group, said group being optionally substituted, and n is 1 or 2; or a salt or ester thereof.

This application is a 371 of PCT/GB00/01294 filed Apr. 4, 2000.

This invention relates to novel compounds having pharmaceuticalproperties.

Certain aminoalkyl bicycloheptanes having a pharmacological effect onthe central nervous system, are disclosed in British Patent 1 586 249.Also, British Patents 1 444 717 and 1 549 174 describe aminoalkylbicyclooctyl derivatives with similar properties.

The compounds of the invention are of the following formula:

in which R¹ and R² are each hydrogen or C₁₋₄ alkyl, or

R¹ and R² together with the nitrogen atom to which they are attachedform an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinogroup, said group being optionally substituted with 1 to 3 C₁₋₄ alkylsubstituents,

R³ is a naphthyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl,quinolinyl or isoquinolinyl group, said group being optionallysubstituted, and n is 1 or 2;

or a salt or ester thereof.

The compounds of the invention and their pharmaceutically acceptablesalts and esters are indicated for use in the treatment of disorders ofthe central nervous system.

In the above formula (I), R¹ and R² are preferably hydrogen or C₁₋₄alkyl.

A C₁₋₄ alkyl group can be methyl, ethyl, or propyl, and can be branchedor unbranched and includes isopropyl and tert. butyl. Preferably R¹ andR² are each hydrogen, methyl or ethyl, and especially hydrogen ormethyl. The —NR¹R² group is most preferably —N(CH₃)₂ or —NH(CH₃).

Compounds of formula (I) are preferably bicycloheptyl derivatives (n is1).

The R³ substituent is attached to the bicyclo ring at certain positionson the substituent, and examples of R³ groups are a-naphthyl,β-naphthyl, 2-, 3-, 5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl, 2-,3-, 5- or 6-benzofuranyl, 2- or 5-benzothiazolyl, 2-, 3-, 6- or7-quinolinyl or 3-, 6- or 7-isoquinolinyl. A naphthyl group ispreferably β-naphthyl. Preferred R³ substituents are β-naphthyl, 2-, 3-,5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl and 2-, 3-, 5- or6-benzofuranyl.

The R³ group can also be substituted, substitution being in one or bothrings, with one or more, preferably 1 to 3, substituents. Preferredsubstituents include C₁₋₄ alkyl, C₁₋₄ alkoxy, carboxy, hydroxy, cyano,halo, trifluoromethyl, —NR′R″ and —CONR′R″ where R′ and R″ are eachhydrogen or C₁₋₄ alkyl.

A preferred value of R³ is optionally substituted β-naphthyl, andespecially unsubstituted β-naphthyl.

A further preferred value of R³ is optionally substituted 2-, 3-,5- or6-benzothienyl.

As indicated above, it is possible to prepare salts of the compound ofthe invention and such salts are included in the invention. Such saltsare preferably the pharmaceutically acceptable, non-toxic salts. Ofspecial interest are acid addition salts, in particular those withsuitable acids, such as those with inorganic acids, for examplehydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, orwith organic acids, such as organic carboxylic acids, for example,maleic, fumaric, tartaric or citric acid.

In addition to the pharmaceutically acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of compounds or in the preparation of other, for examplepharmaceutically acceptable, acid addition salts, or are useful foridentification, characterisation or purification.

It will be appreciated that when a substituent on an R³ group is acidicsuch as, for example, a carboxy group, the opportunity exists foresters. These can be aliphatic or aromatic, being preferably alkylesters derived from C₁₋₄ alkanols, especially methyl and ethyl esters.An example of an ester substituent is —COOR′ where R′ is C₁₋₄ alkyl.

The compounds of the invention contain asymmetric carbon atoms asindicated by asterisks in the following structures:

This asymmetry gives rise to cis- and trans-isomers as well as, in thecase of the bicycloheptyl derivatives, exo- and endo-forms. Thus thebicycloheptyl derivatives exist as trans exo, trans endo, cis exo andcis endo forms, and in each instance R and S enantiomers. In the case ofthe bicyclooctyl derivatives, there are cis and trans derivatives only,each of which exist in R and S enantiomeric form. The compounds can beprepared as racemic mixtures and can conveniently be used a such, butindividual isomers can be isolated by conventional techniques, or arepreferably prepared by chiro-selective methods. Both racemic mixturesand individual isomers are included in the present invention.

A preferred group of compounds of formula (I) above is one in which R¹and R² are each hydrogen or C₁₋₄ alkyl, and R³ is optionally substitutedβ-naphthyl.

A further preferred group of compounds of formula (I) is one in which R¹and R² are each hydrogen or C₁₋₄ alkyl, and R³ is optionally substitutedbenzothienyl.

A preferred group of compounds of the invention can be represented asfollows:

in which R¹ and R² are each hydrogen or C₁₋₄ alkyl, R⁴ and R⁵ are eachC₁₋₄ alkyl, C₁₋₄ alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl,—NR′R″ or —CONR′R″, where R′ and R″ are each hydrogen or C₁₋₄ alkyl, andp and q are each 0 or 1 to 3, such that the sum of p and q is preferably0 or 1 to 3; or a salt thereof. When the naphthyl group is substitutedthere is preferably a single substituent at the 6-position. Of the abovecompounds of formula (Ia), the most preferred are the unsubstitutedcompounds in which p and q are both 0, and furthermore the compounds inwhich n is 1, the bicycloheptyl derivatives, are most preferred.

A further preferred group of compounds of the invention can berepresented as follows:

in which R¹ and R² are each hydrogen or C₁₋₄ alkyl, and R⁶ is C₁₋₄alkyl, C₁₋₄ alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, —NRR″ or —CONR″, where R′ and R″ are each hydrogen or C₁₋₄ alkyl, and p is0 or 1 to 3; or a salt thereof. When p is 2 or 3, the substituents canbe different.

A further preferred group of compounds of the invention can berepresented as follows:

where the bicyclo group is attached at the 5- or 6-position, and inwhich R¹ and R² are each hydrogen or C₁₋₄ alkyl, and R⁶ is C₁₋₄ alkyl,C₁₋₄ alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, —NRR′R″ or—CONR′R″, where R′ and R″ are each hydrogen or C₁₋₄ alkyl, and p is 0, 1or 2; or a salt thereof. When p is 2, the substituents can be different.

As examples of compounds of the invention, and their pharmaceuticallyacceptable salts, in isomeric or racemic form, there are included:

N,N-Dimethyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine

N-Methyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine

[(3-(6-Methoxy-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(1-Benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(1-Benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(1H-Indol-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(6-Fluoro-1-benzothien-2-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(6-Fluoro-2-naphthylbicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(1-Benzothien-7-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamnine

[3-(1-Benzothien-4-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(1-Benzothien-6-yl)bicyclo[2.2.1]hept-2-yl]-N, N-dimethylmethanamine

[3-(3-Methoxy-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(6-Fluoro-1-benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

N,N-Dimethyl-[3-(2-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine

N,N-Dimethyl-[3-(3-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine

[3-(2-Ethyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(2-Fluoro-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(3-Bromo-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(2,3-Dibromo-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[3-(6-Methoxy-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine

[3-(1-Benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine

[3-(1-Benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine

[3-(6-Fluoro-1-benzothien-2-yl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine

[3-(6-Fluoro-2-naphthyl) bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine

N-Methyl-[3-(3-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine

1-{[3-(3-Methoxy-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methyl}pyrrolidine

1-{[3-(6-Fluoro-1-benzothien-2-yl)bicyclo[2.2.1]hept-2-yl]methyl}pyrrolidine

1-{[3-(3-Methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methyl}pyrrolidine

6-{[3-[(Dimethylamino)methyl]bicyclo[2.2.1]hept-2-yl}-2-naphthol

(3-Naphthalen-2-ylbicyclo[2.2.2]oct-2-yl)methanamine

[3-(6-Methoxy-2-naphthyl)bicyclo[2.2.2]oct-2-yl]-N,N-dimethylmethanamine

[3-(1H-Indol-3-yl)bicyclo[2.2.2]oct-2-yl]-N,N-dimethylmethanamine

N,N-dimethyl-[3-(2-naphthyl)bicyclo[2.2.2]oct-2-yl]methanamine

[3-(1-Benzothien-5-yl)bicyclo[2.2-2]oct-2-yl]-N,N-dimethylmethanamine

[3-(1H-indol-5-yl)bicyclo[2.2.2]oct-2-yl]-N,N-dimethylmethanamine

N-methyl-[3-(2-naphthyl)bicyclo[2.2.2]oct-2-yl]methanamine

The invention also includes processes for the production of compounds ofthe formula (I) above by any of the well known methods for preparingsubstituted alkyl amines. For example, they can be made fromintermediates of the formula:

where R³ and n have the values given above, and R⁷ is —CN, —CONR¹R²,—CH₂NCO, —CHO or —COOR⁸ where R⁸ is C₁₋₄ alkyl.

The compounds of formula (II) are readily converted to compounds offormula (I) by reduction, optionally followed by alkylation. In the caseof the nitriles and arnides of formula (II), the reduction is preferablycarried out using a complex hydride reducing agent such as lithiumaluminium hydride or sodium borohydride, whilst in the case of theisocyanates of formula (II), treatment with a concentrated mineral acidsuch as hydrochloric acid produces the desired conversion. The aldehydesand esters of formula (II) may be reductively aminated to the desiredcompounds of formula (I) by reduction to the corresponding alcoholsusing, for example, a complex hydride reducing agent, conversion of thealcohols to the corresponding alkyl or aryl sulphonates by reaction withan alkyl or aryl sulphonyl chloride such as methyl sulphonyl chloride orp.toluene sulphonyl chloride and reaction of the sulphonates with anamine of formula HNR₁R₂. Reductive amination of the aldehydes of formula(II) may also be carried out by catalytic reduction, for example bycatalytic hydrogenation in the presence of an amine of formula HNR₁R₂.

The compounds are most conveniently prepared from the nitriles andamides of formula (II) and these are the preferred intermediates of theinvention. The amides of formula (II) in which R⁷ is —CONR¹R² are novelcompounds and are included as part of the present invention.

A primary amine produced by the above routes may be converted to asecondary or tertiary amine by alkylation. The alkylation may be carriedout in conventional manner, for example by reductive alkylation,reaction with an alkyl halide or sulphate, reaction with an alkylchloroformate followed by reduction of the resultant urethane, or whenmethylation is to be carried out, preferably by reaction with formicacidformaldehyde (Eschweiler-Clarke).

Intermediate compounds of formula (II) where R⁷ is —CN or —CHO canreadily be prepared by a Diels-Alder reaction, by the addition ofcyclopentadiene or cyclohexadiene to a compound of the formulaR³CH═CH—CN or R³CH═CH—CHO, optionally employing, for example,diethylaluminium chloride as catalyst. The reaction is prolonged and hasto be carried out at an elevated temperature, for example, from 100° C.to 200° C., especially about 160° C., yielding bicycloheptenyl orbicyclooctenyl derivatives, which can be catalytically reduced to givethe compounds of formula (II), as illustrated below.

The reaction results in cis- and trans-enantiomers in racemic mixtures,and can be used to produce both the bicycloheptane and bicyclooctanederivatives of formula (I) above.

A reaction which can conveniently be employed to produce chiralenantiomers of the cycloheptyl derivatives utilises Evans chiralauxilliaries as, for example, oxazolidine amide intermediates of theformula:

where R⁹ is alkyl, aryl or aralkyl, from the corresponding a-unsaturatedacid, as follows:

followed by a Diels-Alder reaction with cyclopentadiene in the presenceof a Lewis acid and solvent such as dichloromethane, at a lowtemperature for example between −10° C. and −30° C. The reactionproceeds readily to give a bicycloheptenyl derivative, which onreduction yields the compound of formula (IV) above, as follows:

Alternatively, the intermediates of formula (V) can be prepared (1) byreaction of an acryloyloxazolidine with the appropriately saturated R³leaving species such as an R³ halide, in the presence of PdO, or (2) byreaction of an oxazolidinyl phosphonium halide with the appropriatealdehyde of formula R³CHO in the presence of a base such astriethylamine.

Alternatively, instead of employing a chiral compound of formula (IV),an oxazolidine compound in which R⁹ is hydrogen can be used, togetherwith a chiral catalyst.

The compound of formula (IV) is readily converted by action of lithiumhydroxide and hydrogen peroxide to the free acid, which on reaction withamine and further reduction yields a compound of formula (I), asfollows.

Choice of the appropriate α-unsaturated acid starting material allowsthe production of enantiomerically pure cis- and trans-isomers.

It will be appreciated that substituents on the naphthyl or heterocyclylring can be introduced at the outset, or in the final stages of thesynthesis. Sometimes it will be convenient to convert one substituent toanother as, for example, C₁₋₄ alkoxy to hydroxy, at an intermediatestage or in the final product.

As mentioned above, the compounds of the invention and theirpharmaceutically acceptable salts have useful central nervous systemactivity. The compounds inhibit the uptake of neurotransmitters such asserotonin, dopamine and noradrenalin. They are surprisingly effectiveserotonin reuptake inhibitors, as evidenced by their displacement of[³H] citalopram at the binding sites on membranes derived from ratcortex, as in the test described below (see Example 23). In a similartest, also employing rat cortex membrane, the compounds displacednisoxetine, demonstrating their ability to inhibit noradrenalinreuptake, see Journal of Pharmacology and Experimental Therapeutics Vol.272, No. 3, 1176-1186, 1995. The dopamine reuptake properties of thecompounds of the invention are demonstrated in the test described inMolecular Pharmacology 45: 125-135, using membranes derived from ratstriatum. In this test displacement of WIN 35,428 from its reuptakesite, is measured.

Because of their profile of neurotransmitter reuptake properties, thecompounds of the present invention are indicated for use in treating avariety of conditions such as depression, obesity, bulimia, alcoholism,pain, hypertension, ageing, senile dementia, Alzheimer's, memory loss,attention-deficit hyperactivity disorder, sexual dysfunction,Parkinsonism, anxiety, chronic fatigue syndrome, panic disorders,obsessive compulsive disorder, schizophrenia, gastrointestinaldisorders, headache, cardiovascular disorders, smoking cessation, drugaddiction including cocaine abuse, emesis and sleep disorders.

The compounds of the invention are effective over a wide dosage range,the actual dose administered being dependent on such factors as theparticular compound being used, the condition being treated and the typeand size of mammal being treated. However, the dosage required willnormally fall within the range of 0.01 to 20 mgkg per day, for examplein the treatment of adult humans, dosages of from 0.5 to 100 mg per daymay be used.

The compounds of the invention will normally be administered orally orby injection and, for this purpose, the compounds will usually beutilised in the form of a pharmaceutical composition. Such compositionsare prepared in a manner well known in the pharmaceutical art andcomprise at least one active compound.

Accordingly the invention includes a pharmaceutical compositioncomprising as active ingredient a compound of formula (I) or apharmaceutically acceptable salt or ester thereof, associated with apharmaceutically acceptable excipient. In making the compositions of theinvention, the active ingredient will usually be mixed with a carrier,or diluted by a carrier, or enclosed within a carrier which may be inthe form of a capsule, sachet, paper or other container. The excipientmay be a solid, semi-solid or liquid material which acts as a vehicle,excipient or medium for the active ingredient. Some examples of suitableexcipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches,gum acacia, calcium phosphate, alginates, tragacanth, gelatin syrup,methyl cellulose, methyl- and propyl-hydroxybenzoate, talc, magnesiumstearate or oil. The compositions of the invention may, if desired, beformulated so as to provide quick, sustained or delayed release of theactive ingredient after administration to the patient.

Depending on the route of administration, the foregoing compositions maybe formulated as tablets, capsules or suspensions for oral use andinjection solutions or suspensions for parenteral use or assuppositories. Preferably the compositions are formulated in a dosageunit form, each dosage containing from 0.5 to 100 mg, more usually 1 to100 mg, of the active ingredient.

The following Examples illustrate the synthesis of the compounds ofinvention.

EXAMPLE 1 Ethyl (Z)-3-(2-Naphthyl)prop-2-enoate

To a slurry of magnesium chips (0.62 g, 0.026 mol) in THF (200 ml) underN₂ was added a solution of 2-bromonaphthalene (5 g, 0.024 mol) in THF(10 ml). The mixture was heated under reflux overnight. on cooling,solid ZnBr₂ (3.62 g, 0.016 mol) was added in one portion and theresulting white precipitate left to stir at room temperature for 20hours. DMF (20 ml) was added, followed by bis(acetonitrile)palladium(II) chloride (0.02 g, 0.8 mmol) and ethyl cis-iodoacrylate(1.03 ml, 8.0 mmol).

After 1 hour, 2N HCl was added, the mixture diluted with diethyl etherand washed with a saturated solution of ammonium chloride. The etherealphase was dried and the solvent removed in vaccuo. Chromatography onflash silica gel using hexane:dichloromethane (1:1) gave Ethyl(Z)-3-(2-naphthyl)prop-2-enoate as a white solid, M/e 227 (M+H⁺).

EXAMPLE 2 (Z)-3-(2-Naphthyl)prop-2-enoic Acid

A solution of (Z)-naphthalene-2-acrylic acid ethyl ester (1.38 g, 6.0mmole) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) wastreated with lithium hydroxide (0.88 g, 37 mmol) and heated to 60° C.for 6 hours. On cooling, the organic phase was separated and the.aqueous phase was acidified and extracted with diethyl ether. Theethereal phase was dried and the solvent removed in vaccuo to give(Z)-3-(2-naphthyl)prop-2-enoic acid as a white solid which was usedwithout further purification, Mp 207-209° C.

EXAMPLE 3 3-[(E)-3-Naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one

To a stirred solution of (E)-3-(2-naphthyl)prop-2-enoic acid (10 g, 0.05mole) at −78° C., was added triethylamine (8.42 ml, 0.06 mole) andpivaloyl chloride (7.5 ml, 0.06 mole). Stirring was continued for 1hour. To a stirred solution of oxazolidinone (5.14 g, 0.06 mole) in drytetrahydrofuran (200 ml) at −78° C. was added slowly n-butyl lithium(1.6M in hexanes, 38 ml, 0.06 mole). Stirred for 1 hour. The suspensionof the mixed anhydride was transferred into the oxazolidinone anion bymeans of a canula maintaining the temperature below −60° C. Theresulting reaction mixture was stirred for 2 hours. Water was addedcautiously and the reaction extracted with ethyl acetate. The solventwas washed with brine, dried and evaporated to dryness in-vacuo.Chromatography on flash silica using ethyl acetatehexane (1:1) gave3-[(E)-3-naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one as a whitesolid, M/e 268 (M+H).

Similarly prepared were:

4(R)-3-[(E)-3-naphthalen-2-ylprop-2-enoyl]-4-benzyl-1,3-oxazolidin-2-one,Mp121-123° C.

4(S)-3-[(E)-3-naphthalen-2-ylprop-2-enoyl]-4-benzyl-1,3-oxazolidin-2-one,Mp121-123° C.

3-[(Z)-3-naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one, M/e 268(M+H⁺), 290 (M+Na⁺).

4(R)-3-[(Z)-3-naphthalen-2-ylprop-2-enoyl]-4-benzyl-1,3-oxazolidin-2-one,M/e 358 (M+H⁺).

EXAMPLE 4(4R)-3-[(2E)-3-(1-Benzothien-7-yl)-2-propenoyl]-4-benzyl-1,3-oxazolidin-2-one

To a stirred solution of 7-bromobenzothiophene (3.58 g, 16.80 mmol) indry acetonitrile was added (4R)-3-acryloyl-4-benzyl-1,3-oxazilidin-2-one(4.27 g, 18.48 mmol), followed by tritolylphosphine (1.02 g, 3.36 mmol),palladium acetate (377 mg, 1.68 mmol) and finally triethylamine (4.67ml, 33.60 mmol). The mixture was heated to reflux for 3 hours. Whencool, water was added to quench the reaction. The aqueous phase wasextracted with dichloromethane. The organic phase was washed with brine,dried over magnesium sulphate and concentrated in vacuo. Purificationwas achieved by column chromatography on flash silica, using a mixtureof {fraction (1/9)} of ethyl acetate and hexane as an eluant to give(4R)-3-[(2E)-3-(1-benzothien-7-yl)-2-propenoyl]-4-benzyl-1,3-oxazolidin-2-oneas a yellow solid in 60% yield., M/e 364 (MH+).

EXAMPLE 5 3-[(E)-3-Naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one

To a stirred solution of 4S-4-(benzyl)-2-oxazolidinone (20 g, 0.113 mol)in dried tetrahydrofuran (200 ml) cooled to −780 under nitrogen wasadded dropwise a solution of n-butyl lithium 2.5M in hexane (45.2 ml).After 10 min, chloroacetyl chloride (12.76 g) was added dropwise. Theresulting solution was stirred at −78° for 15 min then allowed to warmto room temperature. After 15 min a saturated solution of ammoniumchloride (100 ml) was added and the mixture concentrated in vacuo. Theresidue was extracted with diethyl ether, the extracts were washed withaqueous ammonium chloride, dried, filtered and evaporated to give acolourless solid (28.9 g).

A solution of the (4S)-4-benzyl-3-(chloroacetyl)-1,3-oxazolidin-2-one(29.08 g 0.11 mol) andtriphenylphosphine (36.1 g, 0.138 mol) in toluene (150 ml) was stirredat room temperature. After 72h a yellow gummy solid of the phosphoniumsalt precipitated. The mixture was decanted and the gum triturated withtoluene and diethyl ether. The residue was dried to a pale yellow solid(46.46 g) of(4S)-4-benzyl-3-[(triphenylphosphino)acetyl]-1,3-oxazolidin-onechloride.

A mixture of (4S)-4-benzyl-3-[(triphenylphosphino)acetyl]-1,3-oxazolidin-one chloride (10 mg, 0.193 mmol),2-naphthaldehyde (30 mg, 0.193 mmol), triethylamine (0.030 ml, 0.212mmol) and 4-(dimethylamino)pyridine in acetonitrile (5 ml) was heatedunder reflux for 24 h. After evaporation, the residue was dissolved inhexaneetherdichloromethane and chromatographed on flash silica elutingwith hexane:ether 3:2 to give a white solid (36 mg, 52%) of3-[(E)-3-Naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one. M/e 358(MH+).

EXAMPLE 6trans-endo-3-[(3-Naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl]-1,3-oxazolidin-2-oneandTrans-exo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl]-1,3-oxazolidin-2-one

To a solution of3-[(E)-3-naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one (2 g, 7.5mmole) in dry dichloromethane (20 ml) at −20° C. was added freshlycracked cyclopentadiene (3.2 g, 37 mmole) and diethylaluminium chloride(5.4 ml, 9.7 mmole). The reaction mixture was stirred for 2 hours. Thereaction was poured into ice water and the solvent separated. Theaqueous was extracted with dichloromethane and the combined solventwashed with brine, dried and evaporated to dryness in-vacuo.Chromatography on flash silica using ethyl acetatehexane (3:7)gavetrans-endo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl]-1,3-oxazolidin-2-one,M/e 334 (M+H⁺), andtrans-exo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl]-1,3-oxazolidin-2-one,M/e 334 (M+H⁺).

Similarly prepared were:

trans-endo-4(R)-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl]-4-benzyl-1,3-oxazolidin-2-one,

Mp135-136° C.

trans-endo-4(S)-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl]-4-benzyl-1,3-oxazolidin-2-one,

Mp135-136° C.

cis-endo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl]-1,3-oxazolidin-2-one,Mp194-196° C.

cis-exo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl)-1,3-oxazolidin-2-one

EXAMPLE 7trans-endo-3-[(3-Naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl]-1,3-oxazolidin-2-one

A solution of the catalyst was prepared under nitrogen by stirringtogether anhydrous copper(ll)chloride (0.0046 g, 0.034×10⁻³ mol),2,2′-isopropylidenebis(4-S)-4-tert-butyl-2-oxazoline (0.012 g,0.038×10⁻³ mol) and silver(ll)hexafluoroantimonate (0.024 g, 0.068×10⁻³mol) in dry dichloromethane (0.34 ml) at room temperature for 8 hours.The solid precipitate was removed by filtration through a celite pad andthe bright blue catalyst solution was added under nitrogen to a stirredslurry of 3-[(E)-3-naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one(0.05 g, 0.0019 mol) in dry dichloromethane (1 ml). Freshly crackedcyclopentadiene (0.2 ml, 0.0023 mol) was added and the mixture stirredat room temperature for 24 hours. After this time, the solvent wasremoved in vacuo and the residue purified by column chromatography,eluent 7:3 hexane:ethyl acetate, to givetrans-endo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl]-1,3-oxazolidin-2-oneas a white solid. Mp 135-136° C.

EXAMPLE 8trans-endo-3-[(3-Naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)carbonyl]-1,3-oxazolidin-2-one

To a solution oftrans-endo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-5-en-2-yl)carbonyl]-1,3-oxazolidin-2-one(1 g, 3 mmole) in ethyl acetate (20 ml) was added 10%Pd—C (0.1 g). Thereaction was hydrogenated at 60 psi using a Parr hydrogenator for 1hour. The catalyst was removed by filtration through celite and thesolvent removed by evaporation in-vacuo. The product was purified bychromatography on flash silica using ethyl acetatehexane (3:7) to givetrans-endo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)carbonyl]-1,3-oxazolidin-2-oneas a colourless oil, M/e 336(M+H⁺).

Similarly prepared were:

trans-exo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-5yl)carbonyl]-1,3-oxazolidin-2-one, M/e 336 (M+H⁺).

trans-endo-4(R)-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)carbonyl]-4-benzyl-1,3-oxazolidin-2-one,Mp141-143° C.

trans-endo-4(S)-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)carbonyl]-4-benzyl-1,3-oxazolidin-2-one,Mp141-143° C.

cis-endo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)carbonyl]-1,3-oxazolidin-2-one.

cis-exo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)carbonyl]-1,3-oxazolidin-2-one.

EXAMPLE 9 trans-endo-3-Naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxylicAcid

To a solution oftrans-endo-3-[(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)carbonyl]-1,3-oxazolidin-2-one(0.29 g, 0.86 mmole) in a mixture of tetrahydrofuran (20 ml) and water(5 ml) at −5° C. was added hydrogen peroxide (2 ml) dropwise. To theresulting slurry was added a solution of lithium hydroxide (42 mg,0.18mmole) in water (5 ml) dropwise, keeping the temperature below 0° C.The resulting mixture was stirred 1 hour at 0° C. and then for 2 hoursat room temperature. The reaction was quenched with a solution of sodiumsulphide in water made acid with 6NHCl and extracted withdichloromethane. The solvent was washed with brine, dried and evaporatedto dryness in-vacuo. Chromatography on flash silica using ethylacetate:hexane (1:1) gavetrans-endo-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxylic acid, M/e267 (M+H⁺).

Similarly prepared were:

trans-exo-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxylic acid, M/e267 (M+H⁺).

trans-endo-(2R,3R)-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxylicacid, Mp135-137° C.

trans-endo-(2S,3S)-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxylicacid, Mp135-137° C.

cis-endo-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxylic acid.

cis-exo-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxylic acid.

EXAMPLE 10 trans-endo-N, N-Dimethyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamide

To a stirred solution oftrans-endo-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxylic acid (225mg) in dichloromethane (5 ml) at 0-5° C. was added oxalyl chloride (81μl, 0.93 mmole) followed by dry dimethylformamide (1 drop). The mixturewas allowed to attain room temperature and stirred for 2 hours. Thesolution was evaporated to dryness in-vacuo, re-dissolved in drytetrahydrofuran and added to a stirred solution of dimethylamine intetrahydrofuran (2M solution, 0.9 ml, 1.7 mmole). The mixture wasstirred for 2-hours. The reaction mixture was diluted with ice-water,extracted with ethyl acetate, washed with water, dried and evaporated todryness in-vacuo. Chromatography on flash silica using ethylacetate:hexane (1:1) gavetrans-endo-N,N-dimethyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamideas a colourless oil, M/e 294 (M+H⁺).

Similarly prepared were:

trans-exo-N,N-dimethyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamide,M/e 294 (M+H⁺).

trans-endo-(2R,3R)-N,N-dimethyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamide,Mp140 -142° C.

trans-endo-(2S,3S)-N,N-dimethyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamide,Mp140 -142° C.

trans-endo-N-methyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamide.

trans-endo-(2R,3R)-N-methyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamide.

trans-endo-(2S,3S)-N-methyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamide,M/e 280 (M+H⁺).

cis-endo-N,N-dimethyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamide.

cis-exo-N,N-dimethyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamide.

EXAMPLE 11(1S,2R,3S,4R)-3-(2-methyl-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide.

To a stirred solution of(1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide(200 mg, 0.67 mmol) in dry tetrahydrofuran (5 mL) at −78° C. was addedlithium diisopropylamide (1.67 mL, 3.35 mmol). The mixture was stirredat this temperature for 1 hour before iodomethane (2.3 mL, 3.35 mmol)was added. The mixture was stirred for another 10 minutes at thistemperature before it was allowed to warm to room temperature. After 1hour, water was added and the layers were separated. The aqueous phasewas extracted with ethyl acetate (2×10 mL) and the extracts were washedwith water (2×10 mL) dried over magnesium sulphate and evaporatedin-vacuo. Column chromatography with 20% ethyl acetate in hexaneprovided the(1S,2R,3S,4R)-3-(2-methyl-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide as a glass (140 mg, 66%). M/e 314 (M+H⁺).

Similarly prepared was:

(1S,2R,3S,4R)-3-(2-ethyl-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide,M/e 328 (MH+).

EXAMPLE 12(1S,2R,3S,4R)-3-(2-Fluoro-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide

To a stirred solution of(1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide (200 mg, 0.67 mmol) in dry tetrahydrofuran(5 mL) at −78° C. was added lithium diisopropylamide (1.67 mL, 3.35mmol). The mixture was stirred at this temperature for 1 hour beforeN-fluorobenzene sulfonimide (2.3 mL, 3.35 mmol) was added. The mixturewas stirred for another 10 minutes at this temperature before it wasallowed to warm to room temperature. After 1 hour, water was added andthe layers were separated. The aqueous phase was extracted with ethylacetate (2×10 mL) and the extracts were washed with water (2×10 mL)dried over magnesium sulphate and evaporated in-vacuo. Columnchromatography with 20% ethyl acetate in hexane provided(1S,2R,3S,4R)-3-(2-fluoro-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide.

mp 159-161 C.

EXAMPLE 13(1S,2R,3S,4R)-3-(3-Bromo-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide

To a solution of(1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide(30 mg, 0.1 mmol) in acetic acid (2 mL) was added bromine (5.5 μL, 0.1mmol) and the mixture was stirred at room temperature for 16 hours. Themixture was diluted with methylene chloride (5 mL) and neutralised bycareful addition of a saturated hydrogen carbonate solution. The layerswere separated and the aqueous was extracted with methylene chloride(2×5 mL). The organic extracts were washed with water, dried overmagnesium sulfate and evaporated in vacuo to give(1S,2R,3S,4R)-3-(3-bromo-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamideas a glass (37 mg, 97%). M/e 378/380 (MH⁺).

Similarly prepared was:

(1S,2R,3S,4R)-3-(2,3-dibromo-1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide,M/e 466/468/470 (MH+).

EXAMPLE 14trans-endo-N,N-Dimethyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine

To a stirred solution oftrans-endo-N,N-dimethyl-3-naphthalen-2-ylbicyclo[2.2.1]heptane-2-carboxamide(0.45 g, 1.53 mmole) in dry ether (20 ml) was added a solution oflithium aluminium hydride in tetrahydrofuran (2M, 0.84 ml, 1.7 mmole).The reaction was heated at reflux for 1 hour. After cooling to roomtemperature water (1 ml) was added dropwise with caution followed by2NNaOH (1 ml). When gas evolution ceased the reaction mixture wasfiltered through a pad of celite which was well washed with ether. Theether solution was dried and after removal of the solvent in-vacuo theproduct was converted to the hydrochloride salt and re-crystallised fromethanolether to givetrans-endo-N,N-dimethyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine,Mp 249-250° C.

Similarly prepared, as hydrochloride or maleate salts, were:

trans-exo-N,N-dimethyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine,M/e 280 (M+H⁺).

trans-endo-N,N-dimethyl[(2R,3R)-3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl]methanamine,α_(D)−44.4 (c 0.5, MeOH, 25° C.).

trans-endo-N,N-dimethyl](2S,3S)-3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl]methanamine,α_(D)+44.4 (c 0.5, M/eOH, 25° C.).

trans-endo-N-methyl (3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine.

trans-endo-N-methyl[(2R,3R)-3-naphthalen-2-ylbicyclo [2.2.1]hept-2-yl]methanamine.

trans-endo-N-methyl[(2S,3S)-3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl]methanamine,mp=210-212° C.

cis-N,N-dimethyl (3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine,mp255-257° C.

N,N-dimethyl[(2R,3R)-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl]methanamine,M/e 280 (MH+).

[(1S,25,3S,4R)-3-(6-methoxy-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,mp=145-146 C.

[(1S,2S,3S,4R)-3-(1-benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,mp=208-210 C.

[(1S,2S,3S,4R)-3-(1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,mp=145-146 C.

[(1S,2S,3S,4R)-3-(1H-indol-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,mp=148-149 C.

[(1S,2S,3S,4R)-3-(6-fluoro-1-benzothien-2-yl)bicyclo[2.2.1]hept-2-yl)-N,N-dimethylmethanamine,M/e 304 (MH+).

[(1S,2S,3S,4R)-3-(6-fluoro-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,mp=137-138 C.

[(1S,2S,3S,4R)-3-(1-benzothien-7-yl)bicyclo [2.2.1]hept-2-yl]-N,N-dimethylmethanamine, M/e 286 (MH+).

[(1S,2S,3S,4R)-3-(1-benzothien-4-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,mp=114-116 C.

[(1S,2S3S,4R)-3-(1-benzothien-6-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,mp=240-242 C.

[(1S,2S,3S,4R)-3-(3-methoxy-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,mp=154-156 C.

[(1S,2S,3S,4R)-3-(6-fluoro-1-benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,M/e 304 (MH+).

N,N-dimethyl[(1R,2R,3R,4S)-3-(3-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine,mp=250-252 C.

N,N-dimethyl[(1S,2S,3S,4R)-3-(2-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine,mp=192-194 C.

[(1S,2S,3S,4R)-3-(2-ethyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,mp=167-169 C.

[(1S,2S,3S,4R)-3-(2-fluoro-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,mp=159-161 C.

[(1S,2S,3S,4R)-3-(3-bromo-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine,M/e 346366 (MH+).

[(1S,2S.3S,4R)-3-(2,3-dibromo-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine, mp=101-107 C.

[(1R,2R,3R,4S)-3-(6-methoxy-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine, mp=208-210 C.

[(1S,2S,3S,4R)-3-(1-benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine,M/e 272 (MH+).

[(1S,2S,3S,4R)-3-(1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine,mp=165-162 C.

[(1S, 2S, 3S, 4R)-3-(6-fluoro-1-benzothien-2-yl)bicyclo(2.2.1]hept-2-yl]-N-methylmethanamine, M/e 290 (MH+).

[(1S,2S,3S,4R)-3-(6-fluoro-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N-methylmethanamine,mp=167-169 C.

N-methyl[(1R,2R,3R,4S)-3-(3-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine,mp=260-262 C.

1-{[(1S,2S,3S,4R)-3-(3-methoxy-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methyl}pyrrolidine,mp=124-126 C.

1-{[(1S,2S,3S,4R)-3-(6-fluoro-1-benzothien-2-yl)bicyclo[2.2.1]hept-2-yl]methyl}pyrrolidine, M/e 330 (MH+).

1-{[(1R,2R,3R,4S)-3-(3-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methyl}pyrrolidine,198-200 C.

EXAMPLE 156-{(1R,2S,3S,4S)-3-[(Dimethylamino)methyl]bicyclo[2.2.1]hept-2-yl}-2-naphthol

To a stirred solution of [(1S,2S,3S,4R)-3-(6-methoxy-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N, N-dimethyl methanamine in DMF was added sodiumethane thionyl. The mixture was heated to 100 C for 40 hours. When cool,water was added to quench the reaction. The aqueous phase was extractedwith ethyl acetate. The organic phase was washed with water, brine,dried over magnesium sulfate and concentrated in-vacuo. Purification wasachieved by column chromatography, using flask silica andDCMM/eOH(M/eOH,NH40H at 10%) in a ration of 10/1/0.1 for eluant. Yield(10%). ME 296 (MH+).

EXAMPLE 16 trans-3-Naphthalen-2-ylbicyclo[2.2.2]oct-5-ene-2-carbonitrile

A mixture of (E)-(2-naphthyl)-acrylonitrile (1.8 g, 0.01 mole) and1,3-cyclohexadiene (8 g, 0.1 mole) in 1,2-dichlorobenzene (10 ml) wasplaced in a teflon lined stainless steel bomb and heated at 180° C. for3 days. The vessel was allowed to cool to room temperature and thecontents transferred to a Buchi flask. The solvent was removed underhigh vacuum and the product purified by chromatography on flash silicaby elution with dichloromethane to givetrans-3-naphthalen-2-ylbicyclo[2.2.2]oct-5-ene-2-carbonitrile, M/e 260(M+H⁺).

Similarly prepared was:

cis-3-naphthalen-2-ylbicyclo[2.2.2]oct-5-ene-2-carbonitrile.

EXAMPLE 17 (2E)-3-(1H-indol-5-yl)-2-propenenitrile

To a stirred solution of 5-iodoindole (2.43 g, 10 mmol) in dryacetonitrile was added acrylonitrile (1.06 g, 20 mmol), followed bytriethylamine (2.02 g, 20 mmol),Palladium acetate (66 mg, 0.3 mmol) andfinally triphenylphosphine (156 mg, 0.6 mmol). The mixture was heated toreflux under N2 atmosphere for 6 hours. Since some starting material wasremaining by TLC, more acrylonitrile (1.06 g, 20 mmol) was added and thereflux was carried on for a further 18 hours.

When cool, the solvent was evaporated to dryness, and the product waspurified by column chromatography on flash silica with DCM to give awhite solid as (2E)-3-(1H-indol-5-yl)-2-propenenitrile in 77% yield. M/e169 (MH+).

EXAMPLE 18 trans-3-Naphthalen-2-ylbicyclo[2.2.2]octane-2-carbonitrile

To a solution oftrans-3-naphthalen-2-ylbicyclo[2.2.2]oct-5-ene-2-carbonitrile (1.2 g) inethyl acetate (50 ml) was added 10% Pd—C (120 mg). The reaction washydrogenated at 60 psi using a Parr hydrogenator for 1 hour. Thecatalyst was removed by filtration through celite and the solventremoved by evaporation in-vacuo. The product was recrystallised fromethyl acetatehexane to givetrans-3-naphthalen-2-ylbicyclo[2.2.2]octane-2-carbonitrile, Mp108-110°C.

Similarly prepared was:

cis-3-naphthalen-2-ylbicyclo [2.2.2]octane-2-carbonitrile.

EXAMPLE 19 trans-(3-Naphthalen-2-ylbicyclo[2.2 .2]oct-2-yl)methanamine

To a stirred solution oftrans-3-naphthalen-2-ylbicyclo[2.2.2]octane-2-carbonitrile(1 g) in dryether (30 ml) was added a solution of lithium aluminium hydride intetrahydrofuran (174 mg). The reaction was heated at reflux for 2 hours.After cooling to room temperature water (1 ml) was added dropwise withcaution followed by 2NNaOH (1 ml). When gas evolution ceased thereaction mixture was filtered through a pad of celite which was wellwashed with ether. After removal of the solvent in-vacuo the product wasconverted to the hydrochloride salt and re-crystallised fromethanolether to givetrans-3-naphthalen-2-ylbicyclo[2.2.2]oct-2-yl)methanamine, mp272-274° C.

Similarly prepared, as hydrochloride or maleate salts, were:

cis-(3-naphthalen-2-ylbicyclo [2.2.2]oct-2-yl)methanamine

[(2R,3R)-3-(6-methoxy-2-naphthyl)bicyclo[2.2.2]oct-2-yl]-N,N-dimethylmethanamine,mp=218-220 C.

[(2R,3R)-3-(1H-indol-3-yl)bicyclo[2.2.2]oct-2-yl]-N,N-dimethylmethanamine,mp=132-134 C.

N,N-dimethyl[(2R,3R)-3-(2-naphthyl)bicyclo[2.2.2]oct-2-yl]methanamine,mp=126-128 C.

N,N-dimethyl[(2S,3S)-3-(2-naphthyl)bicyclo[2.2.2]oct-2-yl]methanamine,mp=128-130 C.

[(2R,3R)-3-(1-benzothien-5-yl)bicyclo[2.2.2]oct-2-yl]-N,N-dimethylmethanamine,mp=63-65 C.

[(2R,3R)-3-(1H-indol-5-yl)bicyclo[2.2.2]oct-2-yl]-N,N-dimethylmethanamine,mp=184-186 C.

N-methyl[(2R,3R)-3-(2-naphthyl)bicyclo[2.2.2]oct-2-yl]methanamine,mp=112-114 C.

N-methyl[(2S,3S)-3-(2-naphthyl)bicyclo[2.2.2]oct-2-yl]methanamine,mp=114-116 C.

EXAMPLE 20 trans-N, N-Dimethyl (3-naphthalen-2-ylbicyclo[2.2.2]oct-2-yl)methanamine

A mixture of trans-(3-naphthalen-2-ylbicyclo[2.2.2]oct-2-yl)methanamine(0.8, mole), 90% formic acid (5 ml) and 40% aqueous formaldehyde (5 ml)in dimethylformamide (10 ml) was heated at reflux for 2 hours. Thereaction was poured into ice water and extracted with diethyl ether. Thesolvent was washed with brine, dried and evaporated to dryness in-vacuo.Chromatography on flash silica by elution with 10%methanol/dichloromethane followed by crystallisation of thehydrochloride salt from ethanol ether gavetrans-N,N-dimethyl(3-naphthalen-2-ylbicyclo[2.2.2]oct-2-yl)methanamine,Mp236-238° C.

Similarly prepared was:

cis-N,N-dimethyl(3-naphthalen-2-ylbicyclo[2.2.2]oct-2-yl)methanamine.

EXAMPLE 21

Tablets each containing 10 mg of active ingredient are made up asfollows:

Active ingredient 10 mg Starch 160 mg Microcrystalline cellulose 100 mgPolyvinylpyrrolidone (as 10% solution in water) 13 mg Sodiumcarboxymethyl starch 14 mg Magnesium stearate 3 mg Total 300 mg

The active ingredient, starch and cellulose are mixed thoroughly. Thesolution of polyvinylpyrrolidone is mixed with the resultant powders andpassed through a sieve. The granules so produced are dried and re-passedthrough a sieve. The sodium carboxymethyl starch and magnesium stearateare then added to the granules which, after mixing, are compressed on atablet machine to yield tablets each weighing 300 mg.

EXAMPLE 22

Capsules each containing 20 mg of medicament are made as follows:

Active ingredient 20 mg Dried starch 178 mg Magnesium stearate 2 mgTotal 200 mg

The active ingredient, starch and magnesium stearate are passed througha sieve and filled into hard gelatine capsules in 200 mg quantities.

EXAMPLE 23 [³H]-Citalopram Binding Assay

The ability of compounds of the invention to displace [³H]-citalopramfrom binding sites on rat cerebral cortical membranes was measured inthe following way:

In each well of a 96 deep well plate was added:

100 ml 2 nM [³H]-citalopram 600 ml 50 mM Tris.HCl pH 7.4 containing 150mM NaCl and 5 mM KCl 100 ml Diluted compound, 50 mM Tris.HCl pH 7.4containing 150 mM NaCl and 5 mM KCl (total binding) or 100 mM fluoxetine(non-specific binding) 200 ml Membrane preparation (0.75 mg protein perml)

The microtitre plates were incubated at 37° C. for 90 minutes followedby filtration through GFB filters soaked in 50 mM Tris.HCl/0.1% (wv)polyethylenimine pH 7.4. The filter was washed 5 times with 50 mMTris.HCl. pH 7.4. The filters were removed, dried and the bound tritiumdetermined by liquid scintillation spectrometry.

The results were analysed using an automatic spline fitting programme toprovide Ki values for each of the compounds. By way of example, thefollowing compounds had a K_(i) of less than 100 nM:

trans-endo-N,N-dimethyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine

trans-exo-N,N-dimethyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine

cis- N,N-dimethyl(3-naphthalen-2-ylbicyclo[2.2.1]hept-2-yl)methanamine

[(1S,2S,3S,4R)-3-(6-fluoro-2-naphthyl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[(1S,2S,3S,4R)-3-(1benzothien-6-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

N-N-dimethyl[(1R,2R,3R,4S)-3-(3-methyl-1-benzothien-5-yl)bicyclo[2.2.1]hept-2-yl]methanamine

[(1S,2S,3S,4R)-3-(6-fluoro-1-benzothien-3-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

[(1S,2S,3S,4R)-3-(6-fluoro-1-benzothien-2-yl)bicyclo[2.2.1]hept-2-yl]-N,N-dimethylmethanamine

trans-endo-N-methyl(3-naphthalen-2-yl)bicyclo[2.2.1]hept-2-yl)methanamine

trans-(3-naphthalen-2-ylbicyclo[2.2.2]oct-2-yl)methanamine

cis-(3-naphthalen-2-ylbicyclo[2.2.2]oct-2-yl)methanamine.

What is claimed is:
 1. A compound of the formula

in which R¹ and R² are each hydrogen or C₁₋₄ alkyl, or R¹ and R²together with the nitrogen atom to which they are attached form anazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholino group,said group being optionally substituted with 1 to 3 C₁₋₄ alkylsubstituents, R³ is a naphthyl, indolyl, benzothienyl, benzofuranyl,benzothiazolyl, quinolinyl or isoquinolinyl group, said group beingoptionally substituted, and n is 1 or 2; or a salt or ester thereof. 2.A compound according to claim 1, in which R¹ and R² are each hydrogen orC₁₋₄ alkyl, and R³ is a naphthyl, indolyl, benzothienyl, benzofuranyl,benzothiazolyl, quinolinyl or isoquinolinyl group, said group beingoptionally substituted.
 3. A compound according to either of claims 1and 2, in which the naphthyl group is β-naphthyl.
 4. A compoundaccording to claim 1, in which R³ is β-naphthyl, 2-,3-,5- or 6-indolyl,2-,3-,5- or 6-benzothienyl, 2-,3-,5- or 6-benzofuranyl, 2- or5-benzothiazolyl, 2-,3-,6- or 7-quinolinyl or 3-,6- or 7-isoquinolinyl,said group being optionally substituted.
 5. A compound according toclaim 4, in which R³ is β-naphthyl, 2-,3-,5- or 6-indolyl, 2-,3-,5- or6-benzothienyl or 2-,3-,5- or 6-benzofuranyl.
 6. A compound according toclaim 2, in which R³ is β-naphthyl, optionally substituted with 1 to 3substituents chosen from C₁₋₄ alkyl, C₁₋₄ alkoxy, carboxy, hydroxy,cyano, halo, trifluoromethyl, —NR′R″ and —CONR′R″ where R′ and R″ areeach hydrogen or C₁₋₄ alkyl.
 7. A compound according to any of claims 1to 6, in which n is
 1. 8. A compound according to claim 1 of the formula

in which R¹ and R² are each hydrogen or C₁₋₄ alkyl, R⁴ and R⁵ are eachC₁₋₄ alkyl, C₁₋₄ alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl,-NR′R″ or —CONR′R″, where R′ and R″ are each hydrogen or C₁₋₄ alkyl, andp and q are each 0 or 1 to 3, such that the sum of p and q is 0 or 1 to3; or a salt thereof.
 9. A compound according to claim 8, in which p andq are both 0, and n is
 1. 10. A compound according to claim 1, in whichR³ is 2-,3-,5- or 6-benzothienyl, optionally substituted with 1 to 3substituents chosen from C₁₋₄ alkyl, C₁₋₄ alkoxy, carboxy, hydroxy,cyano, halo, trifluoromethyl, —NR′R″ and —CONR′R″ where R′ and R″ areeach hydrogen or C₁₋₄ alkyl.
 11. A compound according to claim 1 of theformula

in which R¹ and R² are each hydrogen or C₁₋₄ alkyl, and R⁶ is C₁₋₄alkyl, C₁₋₄ alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl,-NR′R″ or -CONR′R″, where R′ and R″ are each hydrogen or C₁₋₄ alkyl, andp is 0 or 1 to 3; or a salt thereof.
 12. A compound according to claim 1of the formula

where the bicyclo group is attached at the 5- or 6-position, and inwhich R¹ and R² are each hydrogen or C₁₋₄ alkyl, and R⁶ is C₁₋₄ alkyl,C₁₋₄ alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, —NR′R″ or—CONR′R″, where R′ and R″ are each hydrogen or C₁₋₄ alkyl, and p is 0, 1or 2; or a salt thereof.
 13. A compound of the formula

where R³ and n have the values defined in claim 1, and R⁶ is —CONR¹R²,where R¹ and R² are each hydrogen or C₁₋₄ alkyl, or a salt thereof. 14.A pharmaceutical formulation comprising a compound according to claim 1or a pharmaceutically acceptable salt or ester thereof, together with apharmaceutically acceptable diluent or carrier therefor.
 15. A compoundaccording to claim 1, or a pharmaceutically acceptable salt or esterthereof, for use as a pharmaceutical.
 16. A method of treating adisorder of the central nervous system which comprises administering aneffective amount of a compound according to claim 1, or apharmaceutically-acceptable salt or ester thereof.